A unique thymus-derived regulatory T cell subset associated with systemic lupus erythematosus

Abstract

Background: Foxp3 is a marker for regulatory T cells (Treg cells), but recent studies have shown the plasticity and heterogeneity of CD4 + Foxp3 + T cells. This study aimed to examine the phenotype and function of circulating CD4 + Foxp3 + T cells in patients with systemic lupus erythematosus (SLE). Methods: We enrolled 47 patients with SLE, 31 with organ-specific autoimmune diseases (15 with multiple sclerosis and 16 with primary immune thrombocytopenia), and 19 healthy subjects. Peripheral blood mononuclear cells were used to evaluate the proportion and phenotype of CD4 + Foxp3 + cells using multicolor flow cytometry, the status of the Treg-specific demethylated region (TSDR) of the foxp3 gene by methylation-specific polymerase chain reaction, and the immunoregulatory function of CD4 + CD25 + cells by allogeneic mixed lymphocyte reaction. Immunohistochemistry of renal biopsy specimens obtained from 6 patients with lupus nephritis and 5 with IgA nephropathy was conducted to detect IL-17A-expressing CD4 + Foxp3 + cells.Results: CD4 + Foxp3 + T cells were increased in SLE patients compared with organ-specific autoimmune disease controls or healthy controls. Circulating CD4 + Foxp3 + T cells were correlated with the disease activity of SLE. The increased CD4 + Foxp3 + T cells in active SLE patients were mainly derived from thymus-derived Treg (tTreg) cells, as determined by a demethylated TSDR status, and represented a unique phenotype, upregulated expression of CD49d, CD161, and IL-17A, with immunosuppressive ability comparable to that of healthy controls. Finally, CD4 + Foxp3 + IL-17A + cells were infiltrated into the renal biopsy specimens of patients with active lupus nephritis. Conclusions:A unique tTreg subset with dichotomic immunoregulatory and T helper 17 phenotypes is increased in the circulation of SLE patients and may be involved in the pathogenic process of SLE.

Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis

“…These findings suggest avenues for the treatment of autoimmunity based on selectively exploiting the exhausted phenotype of tissue-infiltrating T cells in SLE [ 42 ]. Hironari Hanaoka et al [ 43 ] found that CD4 + Foxp3 + IL-17A + cells were infiltrated into the renal biopsy specimens of patients with active lupus nephritis. Liao et al [ 44 ] confirmed through in vivo experiments that renal-infiltrating CD11c + cells are pathogenic in murine lupus nephritis through promoting CD4 + T cell responses.…”

Kidney Tertiary Lymphoid Structures in Lupus Nephritis Develop into Large Interconnected Networks and Resemble Lymph Nodes in Gene Signature

“…44,45 Interestingly, in recently published data, a unique thymus-derived Treg population was found to be increased in patients with SLE. 46 Hanaoka et al 46 also found infiltration of these Tregs within kidney biopsies from patients with active LN. The results from our comparison to the human single-cell gene expression data indicated a similar finding.…”

Exploration of Potential Integrated Models of N6-Methyladenosine Immunity in Systemic Lupus Erythematosus by Bioinformatic Analyses

“…For example, kidney-infiltrating T cells (KITs), as activated effector cells, may cause organ failure and tissue damage (64). CD4 + Foxp3 + IL-17A + cell infiltration was found in renal biopsy specimens of active lupus nephritis (65). Moreover, urinary CD11c+ macrophages expressed proinflammatory cytokines (IL-6 and IL-1) and resembled infiltrated monocytes (66).…”